Methods and compositions for stable liquid drug formulations

ABSTRACT

The invention features a powdered composition including a pharmaceutically active compound and a protein or a hydrolyzed protein. In particular, the powdered composition forms a stable solution or dispersion suitable for oral administration in which the protein or the hydrolyzed protein is bound to the pharmaceutically active compound. The invention also provides a method of administering the composition, such as to a patient with dysphasia; liquid or semi-solid formulations of the composition; methods for preparing the composition; and kits including the composition.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/287,988, filed Dec. 18, 2009.

BACKGROUND OF THE INVENTION

The present invention relates to liquid formulations of pharmaceuticallyactive compounds. In particular, the invention relates to liquidformulations prepared by admixing a liquid with a powdered composition.The resulting liquid formulation is a stable solution or dispersion inwhich the protein is bound to the pharmaceutically active compound. Theprotein can be full length or various hydrolyzed fragments thereof. Alsoprovided herein are methods for preparing the powdered composition, aswell as kits for preparing the liquid formulation.

Though only encompassing about 13% of the general population, elderlypatients account for around 33% of all prescribed medications. Theaverage ambulatory senior takes almost six medications simultaneously,while a nursing home patient may take seven to ten medications. Ingeneral, a larger pill (e.g., a capsule, a gel cap, or a tablet) resultsin greater difficulty in swallowing the medication. For the elderly,swallowing medications can be difficult or painful, a condition commonlyreferred to as dysphagia, which can lead to low compliance by thepatient. Dysphagia is also associated with several chronic diseases,including neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease, etc.), psychiatric diseases, metabolic diseases,and endocrine diseases. It can also be a problem for patients receivingradiation or chemotherapy.

For patients suffering from dysphagia who are on medication, it iscommon practice for the patient or healthcare professional to crush themedication and mix it into a favorite liquid or soft food, such asapplesauce, for consistency and taste masking. In some instances,multiple medications may be crushed and then mixed together within thepatient's food or drink. While compliance may be increased by thispractice, dose strength, drug stability, and pharmacokinetics arecompromised, adversely affecting the efficacy of the medication.

Liquid formulations have been widely used for pediatric medications toprovide for easier administration. These formulations are well known inthe art and are exemplified by, for example, various antibiotics, suchas amoxicillin, augmentin, and gatifloxacin; antiasthmatics, such aszafirlukast (Accolate®); and antivirals, such as zidovudine, lamivudine,stavudine, and abacavir. By contrast, little systematic effort has beenmade to develop liquid formulations for geriatric patients or otheradult patients with swallowing difficulties. In practice, a compoundingpharmacist may attempt to make a liquid formulation for an olderpatient, but no consistent and reliable method has been developed forall drug products.

The above-mentioned problems lead to sub-optimal and/or erratic dosing,which may affect disease progression and lead to an increase in longterm health care. Thus, there is a need for stable and effective liquidformulations for delivering a variety of pharmaceutical agents.

SUMMARY OF THE INVENTION

In a first aspect, the invention features a method of administering apharmaceutically active compound to a patient, the method including thesteps of: providing a powdered composition including a pharmaceuticallyactive compound and a protein or a hydrolyzed protein, where the proteinor the hydrolyzed protein is from 500 Da to 10,000,000 Da; mixing thepowdered composition with a liquid or semi-solid to form a stablesolution or dispersion in which the protein or the hydrolyzed protein isbound to the pharmaceutically active compound; and orally administeringthe solution or dispersion to the patient.

In one embodiment of the first aspect, the method includes thepharmaceutically active compound and the protein or the hydrolyzedprotein present in a ratio of from 1:1 to 1:1,000. In anotherembodiment, the composition includes 1% to 30% (w/w) thepharmaceutically active compound and 90% to 99% (w/w) of the protein orthe hydrolyzed protein. In yet another embodiment, the protein or thehydrolyzed protein is from 500 Da to 1,000,000 Da.

In another embodiment of the first aspect, the invention features amethod where the composition is denatured or partially denatured. In oneembodiment, the size of the powder is from 1 to 100 mesh. In yet anotherembodiment, the invention features a method where the liquid is water oran aqueous solution.

In an embodiment of the first aspect, the invention features a methodwhere the viscosity of the dispersion is from 1 cP to 450 cP. In anotherembodiment, the viscosity of the dispersion is from 50,000 cP to 200,000cP.

In a further embodiment of the first aspect, the pharmaceutically activecompound is less than 500 Da.

In a particular embodiment, the pharmaceutically active compound is oneor more of a 5-HT_(1A) receptor agonist, a 5-HT₂ receptor antagonist, anα-adrenergic receptor agonist, an α-adrenergic receptor antagonist,α-adrenergic receptor agonist, a β-adrenergic receptor antagonist, anacetylcholinesterase inhibitor, an anesthetic, an angiotensin receptorantagonist, an angiotensin converting enzyme inhibitor, an antibiotic,an anticholinergic agent, an anticoagulant, an anticonvulsant, anantidepressant, an antidiabetic agent, an antifungal agent, anantiinflammatory agent, an antihistamine, an antipsychotic agent, anantiplatelet agent, an antiviral agent, an anxiolytic agent, acholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, aneicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, amonoamine oxidase B inhibitor, an N-methyl d-aspartate receptorantagonist, a norepinephrine reuptake inhibitor, a prostaglandin, aproton pump inhibitor, a renin antagonist, a serotonergic, a steroidalanti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, atriptan, a vasodilator, or a nutraceutical.

In another embodiment of the first aspect, the invention features amethod where the protein or the hydrolyzed protein is one or more ofgelatin (e.g., type A gelatin and type B gelatin), cascin, whey protein(e.g., alpha-lactalbumin, beta lactoglobulin, bovine serum albumnin, aglycomacropeptide, immunoglobulin, lactoferrin, and lactoperoxidase),albumin (e.g., bovine serum albumin and human serum albumin), or soyprotein (e.g., β-conglycinin and glycinin). In a further embodiment, theprotein or the hydrolyzed protein includes from 70% to 95% (w/w) of wheyprotein or from 80% to 95% (w/w) of casein.

In a further embodiment of the first aspect, the invention features amethod where the composition further includes one or more agentsselected from the group consisting of an absorption enhancing agent(e.g., achitosan, type A gelatin, and type B gelatin), an antimicrobial(e.g., methylparaben, propylparaben, sodium benzoate, propyl benzoate,sodium sorbate, potassium sorbate, and calcium sorbate), an antioxidant(e.g., methylparaben, propylparaben, sodium benzoate, propyl benzoate,sodium sorbate, potassium sorbate, and calcium sorbate), a bufferingagent (e.g., citric acid, malic acid, tartaric acid, phosphoric acid,and pharmaceutically acceptable salts thereof), a colorant, a dispersingagent (e.g, polyvinylpyrrolidine, an alkyhydroxy cellulose, a dextrin, acyclodextrin, and a polyhydroxyalcohol), a flavoring agent, apreservative (e.g., ethylenediaminetetraacetic acid and a 4-hydroxybenzoic ester), a solubilizing agent (e.g., 200 Da to 1000 Dapolyethylene glycol, sorbitol, a glycol polyol, and dipropylene glycolpolyethylene), a stabilizing agent (e.g., glycerin, pentaerythritol, andsodium alginate), a surfactant (e.g., polyoxylglyceride, a caprylate, alaurate, an oleate, a monoethyl ether, a sorbitan-based nonionicsurfactant, a polyoxyethylene sorbitan-based surfactant, an emulsifierblend, and tocopherol polyethyleneglycol 1000 succinate), a sweetener(e.g., L-aspartylyphenylalanine methyl ester, a stevia saccharin salt, acyclamate salt, acefulfam-K, aspartame, sucralose, a glycyrrhizanate,glucose, xylose, ribose, mannose, fructose, dextrose, sorbitol,mannitol, thymidine, and monellin), a taste masking agent (e.g., sodiumalginate, xanthum gum, carageenan, hydroxypropylmethyl cellulose, methylcellulose, microcrystalline cellulose, or sodium carboxy methylcellulose), a viscosity controlling agent (e.g., gelatin, alginic acid,agarose, agar, carrageenan, xanthan gum, locust bean gum, guar gum,tragacanth, gum karaya, natural gum, methyl cellulose, glucomannan,galactomannan, and gulaman), and a vitamin. In a further embodiment, theamount of the buffering agent results in the dispersion having a pH from6 to 8. In yet a further embodiment, the pH is from 6.8 to 7.2.

In a second aspect, the invention features a powdered compositionincluding a pharmaceutically active compound, and a protein or ahydrolyzed protein of greater than 500 kDa, where the composition whenadmixed with a liquid or semi-solid forms a stable solution ordispersion suitable for oral administration in which the protein or thehydrolyzed protein is bound to the pharmaceutically active compound.

In one embodiment of the second aspect, the pharmaceutically activecompound and the protein or the hydrolyzed protein are present in aratio of from 1:1 to 1:1000.

In another embodiment of the second aspect, the composition includes 1%to 30% (w/w) the pharmaceutically active compound and 90% to 99% (w/w)of the protein or the hydrolyzed protein. In a further embodiment, thecomposition is denatured or partially denatured. In yet anotherembodiment, the size of the powder is from 1 to 100 mesh. In oneparticular embodiment, the liquid is water or an aqueous solution.

In one embodiment of the second aspect, the viscosity of the dispersionis from 1 to 450 cP. In another embodiment, the viscosity of thedispersion is from 50,000 cP to 200,000 cP.

In one embodiment of the second aspect, the invention features apowdered composition where the pharmaceutically active compound isgreater than 500 Da. In a further embodiment, the pharmaceuticallyactive compound is one or more a 5-HT_(1A) receptor agonist, a 5-HT₂receptor antagonist, an α-adrenergic receptor agonist, an α-adrenergicreceptor antagonist, a 0-adrenergic receptor agonist, a β-adrenergicreceptor antagonist, an acetylcholinesterase inhibitor, an anesthetic,an angiotensin receptor antagonist, an angiotensin converting enzymeinhibitor, an antibiotic, an anticholinergic agent, an anticoagulant, ananticonvulsant, an antidepressant, an antidiabetic agent, an antifungalagent, an antiinflammatory agent, an antihistamine, an antipsychoticagent, an antiplatelet agent, an antiviral agent, an anxiolytic agent, acholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, aneicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, amonoamine oxidase B inhibitor, an N-methyl d-aspartate receptorantagonist, a norepinephrine reuptake inhibitor, a prostaglandin, aproton pump inhibitor, a renin antagonist, a serotonergic, a steroidalanti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, atriptan, a vasodilator, or a nutraceutical.

In another embodiment of the second aspect, the protein or thehydrolyzed protein is one or more of gelatin (e.g., type A gelatin andtype B gelatin), casein, whey protein (e.g., alpha-lactalbumin, betalactoglobulin, bovine serum albumin, a glycomacropeptide,immunoglobulin, lactoferrin, and lactoperoxidase), albumin (e.g., bovineserum albumin and human serum albumin), or soy protein (e.g.,3-conglycinin and glycinin). In a further embodiment, the protein or thehydrolyzed protein includes from 70% to 95% (w/w) of whey protein orfrom 80% to 95% (w/w) of casein.

In a further embodiment of the second aspect, the invention features acomposition further including one or more agents selected from the groupconsisting of an absorption enhancing agent (e.g., achitosan, type Agelatin, and type B gelatin), an antimicrobial (e.g., methylparaben,propylparaben, sodium benzoate, propyl benzoate, sodium sorbate,potassium sorbate, and calcium sorbate), an antioxidant (e.g.,methylparaben, propylparaben, sodium benzoate, propyl benzoate, sodiumsorbate, potassium sorbate, and calcium sorbate), a buffering agent(e.g., citric acid, malic acid, tartaric acid, phosphoric acid, andpharmaceutically acceptable salts thereof), a colorant, a dispersingagent (e.g, polyvinylpyrrolidine, an alkyhydroxy cellulose, a dextrin, acyclodextrin, and a polyhydroxyalcohol), a flavoring agent, apreservative (e.g., ethylenediaminetetraacetic acid and a 4-hydroxybenzoic ester), a solubilizing agent (e.g., 200 Da to 1000 Dapolyethylene glycol, sorbitol, a glycol polyol, and dipropylene glycolpolyethylene), a stabilizing agent (e.g., glycerin, pentacrythritol, andsodium alginate), a surfactant (e.g., polyoxylglyceride, a caprylate, alaurate, an oleate, a monoethyl ether, a sorbitan-based nonionicsurfactant, a polyoxyethylene sorbitan-based surfactant, an emulsifierblend, and tocopherol polyethyleneglycol 1000 succinate), a sweetener(e.g., L-aspartylyphenylalanine methyl ester, a stevia saccharin salt, acyclamate salt, acefulfam-K, aspartame, sucralose, a glycyrrhizanate,glucose, xylose, ribose, mannose, fructose, dextrose, sorbitol,mannitol, thymidine, and monellin), a taste masking agent (e.g., sodiumalginate, xanthum gum, carageenan, hydroxypropylmethyl cellulose, methylcellulose, microcrystalline cellulose, or sodium carboxy methylcellulose), a viscosity controlling agent (e.g., gelatin, alginic acid,agarose, agar, carrageenan, xanthan gum, locust bean gum, guar gum,tragacanth, gum karaya, natural gum, methyl cellulose, glucomannan,galactomannan, and gulaman), and a vitamin. In a further embodiment, theamount of the buffering agent results in the dispersion having a pH from6 to 8. In yet a further embodiment, the pH is from 6.8 to 7.2.

In a third aspect, the invention features a liquid or semi-solidformulation prepared by mixing the powdered composition described hereinwith a liquid or semi-solid. In one embodiment, the liquid is an aqueoussolution. In another embodiment, pH is between 6 and 8 (e.g., between6.8 and 7.2). In yet another embodiment, the viscosity is from 1 cP to450 cP or from 50,000 cP to 200,000 cP.

In a fourth aspect, the invention features a method for preparing apowdered composition including: dispersing a protein or a hydrolyzedprotein in an aqueous solution at a first temperature ranging from 10°C. to 50° C. to form a protein mixture; adding an effective amount of apharmaceutically active compound to the protein mixture; before or afterthe compound has been added to the protein mixture, heating the proteinmixture to a second temperature ranging from 23° C. to 60° C., where theamount of the protein or the hydrolyzed protein is in excess of theeffective amount of the compound; cooling the mixture to a thirdtemperature ranging from 5° C. to 23° C.; and separating the mixturefrom the aqueous solution to obtain the powdered composition.

In one embodiment of the fourth aspect, the protein or the hydrolyzedprotein is one or more of gelatin, casein, whey protein, albumin, or soyprotein. In another embodiment, the aqueous solution is water or abuffer. In a further embodiment, the buffer has a pH between 6 and 8.

In another embodiment of the fourth aspect, the method includes anaqueous solution that further includes one or more agents selected fromthe group consisting of an absorption enhancing agent, an antimicrobial,an antioxidant, a buffering agent, a colorant, a dispersing agent, aflavoring agent, a preservative, a solubilizing agent, a stabilizingagent, a surfactant, a sweetener, a taste masking agent, a viscositycontrolling agent, and a vitamin.

In one embodiment of the fourth aspect, the first temperature range isfrom 20° C. to 25° C. In another embodiment, the second temperaturerange is from 25° C. to 37° C. In yet another embodiment, the thirdtemperature range is from 23° C. to 37° C.

In a fifth aspect, the invention features a kit including a powderedcomposition that can be admixed with a liquid to form a stable solutionor dispersion suitable for oral administration to a patient, saidcomposition including: 1% to 30% (w/w) of a pharmaceutically activecompound and 70% to 99% (w/w) of a protein or a hydrolyzed protein ofgreater than 500 kDa, where said compound is bound to said protein; aliquid; and instructions on admixing the powdered composition with theliquid. In one embodiment, the powdered composition includes thepharmaceutically active compound selected from the group consisting of a5-HT_(1A) receptor agonist, a 5-HT₂ receptor antagonist, an α-adrenergicreceptor agonist, an α-adrenergic receptor antagonist, a β-adrenergicreceptor agonist, a β-adrenergic receptor antagonist, anacetylcholinesterase inhibitor, an anesthetic, an angiotensin receptorantagonist, an angiotensin converting enzyme inhibitor, an antibiotic,an anticholinergic agent, an anticoagulant, an anticonvulsant, anantidepressant, an antidiabetic agent, an antifungal agent, anantiinflammatory agent, an antihistamine, an antipsychotic agent, anantiplatelet agent, an antiviral agent, an anxiolytic agent, acholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, aneicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, amonoamine oxidase B inhibitor, an N-methyl d-aspartate receptorantagonist, a norepinephrine reuptake inhibitor, a prostaglandin, aproton pump inhibitor, a renin antagonist, a serotonergic, a steroidalanti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, atriptan, a vasodilator, or a nutraceutical. In another embodiment, thepowdered composition includes the protein or the hydrolyzed proteinselected from the group consisting of gelatin, casein, whey protein,albumin, and soy protein.

In yet another embodiment of the fifth aspect, the liquid includes oneor more agents selected from the group consisting of an absorptionenhancing agent, an antimicrobial, an antioxidant, a buffering agent, acolorant, a dispersing agent, a flavoring agent, a preservative, asolubilizing agent, a stabilizing agent, a surfactant, a sweetener, ataste masking agent, a viscosity controlling agent, and a vitamin.

Definitions

As used herein, “bound” and “binding” refers to a non-covalent or acovalent interaction that holds two molecules together. For example, twosuch molecules could be a pharmaceutically active compound and aprotein. Non-covalent interactions include, but are not limited to,hydrogen bonding, ionic interactions among charged groups, electrostaticbinding, van der Waals interactions, hydrophobic interactions amongnon-polar groups, lipophobic interactions, and Log P-based attractions.

By “complex” is meant a pharmaceutically compound bound to a full lengthprotein or a hydrolyzed protein.

By “drug class protein” is meant a protein that binds a class ofpharmaceutically active compounds.

As used herein, the phrase “an effective amount of a pharmaceuticallyactive compound” refers to an available amount of one or more compoundsin a liquid formulation that will provide a therapeutic benefit to apatient.

By “pharmacophore” is meant a functional group present in apharmaceutically active compound that imparts its therapeutic function.

By “stable dispersion” is meant a dispersion that stabilizes apharmaceutically active compound that is admixed in a liquid or in asemi-solid food product.

By “patient” is meant a mammal, including, but not limited to, a humanor non-human mammal.

By “hydrolyzed protein” is meant a protein fragment formed by breakingof one or more peptide bonds in a full length protein.

The recitation herein of numerical ranges by endpoints is intended toinclude all numbers subsumed within that range (e.g., a recitation of 1to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

As used herein, “a” or “an” means “at least one” or “one or more” unlessotherwise indicated. In addition, the singular forms “a”, “an”, and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to a composition containing “acompound” includes a mixture of two or more compounds.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph showing antinociception (reduction in pain) over timein mice treated with 10 mg/kg, 3.2 mg/kg, or 1 mg/kg fentanyl formulatedin water.

FIG. 1B is a graph showing antinociception over time in mice treatedwith 10 mg/kg, 3.2 mg/kg, or 1 mg/kg fentanyl formulated in a boundstate with Bovine Serum Albumin (BSA).

FIG. 2 is a graph comparing the antinociception over time in micetreated with fentanyl formulated in water versus fentanyl bound to RSA.The data show that fentanyl bound to BSA produced a greater analgesicresponse than fentanyl formulated in water (compare the results for 1mg/kg and 3.2 mg/kg fentanyl in water vs. the BSA formulation).

FIG. 3 is a graph showing the absorption profile for ketoprofenadministered in saline or bound to BSA.

DETAILED DESCRIPTION

This invention features a powdered composition that contains a complexof a pharmaceutically active compound and a protein, typically ahydrolyzed protein. The powdered composition can be mixed with a liquidmedium and reconstituted to provide a stable liquid solution ordispersion of the pharmaceutical agent suitable for oral consumption bya patient who has difficulty swallowing pills. The invention usesproteins as universal acceptors of organic molecules, such aspharmaceutically active compounds, with molecular weights preferablyunder 500 Daltons (Da). The invention can be applied to virtually allpharmaceutically active compounds that bind plasma protein.Surprisingly, this is true whether the compound is lipophilic, charged,or neutral. The ability of proteins to serve as such universal acceptorsstems from the complicated physical chemistry and geometry of structuralproteins. Plasma proteins (e.g., in humans and animals) and proteinsfrom other sources, whether synthetic or natural, have many differentbinding zones that allows for tight binding of charged and non-chargedmolecules. Stated differently, proteins have anionic, cationic, andlipophilic sites that allow binding of all types of organic moleculesand salts of organic molecules to these proteins. By using these variousbinding zones and sites, a complex can be formed between apharmaceutically active compound and a protein.

Methods of Preparing the Powder Composition and Liquid FormulationMethods are provided herein for preparing powder compositions, which canbe combined with a liquid to provide a stable solution or dispersion ofa pharmaceutically active compound. The method of the invention can beused to stabilize a wide variety of pharmaceutically active compoundsthat are generally considered to be unstable in liquid media, such asesters of drugs.

Such compounds can be difficult to provide as a liquid formulation for anumber of reasons. For example, the liquid media often leads tohydrolysis of the drug over time. The present invention addresses theseproblems by combining the drug with, for example, a hydrolyzed orpartially hydrolyzed protein. The binding of the drug to the proteintakes the drug out of solution and thus stabilizes the molecule fromdegradation. This method is applicable to all drugs, nutraceuticals, ornutrition aids that may be charged (cationic or anionic), neutral,lipophilic, or zwitterionic. It can also be applied to hydrophobic andhydrophilic drugs, all salt forms of drugs, all polymorphic forms, andother drugs not normally stable in liquid media.

Generally, the method for preparing the powdered composition includesthe following steps of:

dispersing a hydrolyzed protein in an aqueous solution to form a proteinmixture, wherein this step may be performed at room temperature 23° C.or at an elevated temperature that drives solubilization withoutdenaturation and the optimal temperature can be determined for eachprotein using known methods;

adding an effective amount of a pharmaceutically active compound to theprotein mixture and heating the mixture to bind the drug to the protein,wherein the amount of the protein is typically in excess of theeffective amount of the compound, wherein this step is performed at anoptimal temperature for solubilization (e.g., between 23° C. and 60°C.);

cooling the mixture (e.g., to a temperature between 5° C. and 23° C.);and

separating the mixture from the aqueous solution to obtain the powderedcomposition (e.g., by filtration or centrifugation).

The method can include additional steps and modifications. For example,once separation has been completed, the resulting products may befurther dried by lyophilization to a dehydrated powder. This powder canthen be reconstituted in an aqueous solution with standard components,such as those excipients commonly used to optimize color, viscosity,taste characteristics, and antimicrobials.

In another example, the aqueous solution can include additionalcomponents, such as an absorption enhancing agent, an antimicrobial, anantioxidant, a buffering agent, a colorant, a dispersing agent, aflavoring agent, a preservative, a solubilizing agent, a stabilizingagent, a surfactant, a sweetener, a taste masking agent, a viscositycontrolling agent, a vitamin, or any other additive or agent describedherein. In addition, further steps may be included in the process to addother additives or agents.

Examples of other additive or agents that may be used in thecompositions of the invention include, but are not limited to,absorption enhancing agents, adjuvants, antimicrobials, antioxidants,buffering agents, chelating agents, demulcents, demulsifiers,deodorants, detergents, dispersing agents, dyes emulsifiers, fillers,gelling agents, inert diluents (e.g., calcium carbonate, sodiumcarbonate, lactose, calcium phosphate, sodium phosphate, or kaolin),phytomedicinals, plasticizing agents, preservatives, solvents,solubilizing agents, stabilizing agents, surfactants, thickeners (e.g.,xanthan gum, a fatty acid, a fatty acid salt or ester, a fatty alcohol,a modified cellulose, a modified mineral material, or a syntheticpolymer), viscosity controlling agents, vitamins, or wetting agents.

Exemplary absorption enhancing agents, such as for polar molecules,include, but are not limited, to chitosan, type A gelatin, and type Bgelatin.

Exemplary antimicrobials include parabens (e.g., methylparaben andpropylparaben), benzoates (e.g., sodium benzoate and propyl benzoate),and sorbates (e.g., sodium sorbate, potassium sorbate, and calciumsorbate).

Exemplary antioxidants include, but are not limited to, vitamin C,vitamin E, or mixtures of natural tocopherols.

Exemplary buffering agents include, but are not limited to, citric acid,malic acid, tartaric acid, phosphoric acid, or their salts forms, thatwhen used with other agents or compounds produces a stable pH between 6and 8 and most preferably between 6.8 and 7.2.

Exemplary dispersing agents include, but are not limited to,polymer-based dispersing agents, such as polyvinylpyrrolidine (PVD);alkyhydroxy celluloses, such as hydroxypropylmethyl cellulose; variousdextrins and cyclodextrins, such as hydroxpropyl-beta-cyclodextrin andhydroxypropyl-gamma-cyclodextrin; and all GRAS polyhydroxyalcohols.

Exemplary preservatives include, but are not limited to,ethylenediaminetetraacetic acid or one or more 4-hydroxy benzoic acidesters, such as methyl, ethyl, propyl and butyl analogs.

Exemplary solubilizing agents include, but are not limited to,polyhedric alcohols, such as polyethylene glycol with weights rangingbetween 200 and 1000 Da, and most preferably PEG 200, 400 and 600 aloneor in combination with sorbitol, dipropylene glycol polyethylene, otherglycol polyols, ethanol, and ethylenediaminetetraacetic acid (EDTA).Exemplary stabilizing agents include, but are not limited to, glycerin,pentaerythritol, or sodium alginate.

Exemplary surfactants include, but are not limited to,polyoxylglycerides, such as Labrafril®M 1944 CS (oleoylmacrogolglycerides), Labrafril®M 2125 CS (linoleoyl macrogolglycerides),Labrasol® (caprylocaproyl macrogolglycerides); caprylates, such asCapryol™ 90 (propylene glycol monocaprylate), and Capryol™ PGMC(propylene glycol caprylate); laurates, such as Lauroglycol™ 90(propylene glycol monolaurate) and Lauroglycol™ FCC (propylene glycollaurate); oleates, such as Plurol® Oleique CC497 (polyglyceryl oleate);monoethyl ethers, such as Transcutol® HP (diethylene glycol monoethylether); sorbitan-based nonionic surfactants, such as Span® 20 (sorbitanmonolaurate), Span® 80 (sorbitan oleate), and Span® 85 (sorbitantrioleate), including polyoxyethylene sorbitan-based surfactants, suchas Tween® 60 (polysorbate 60) and Tween® 80 (polysorbate 80); emulsifierblends, such as Tandem® 552/522 K (mono-diglycerides and polysorbate 60)and Atmos® 300K (mono-diglycerides and propylene glycol); and tocopherolpolyethyleneglycol 1000 succinate.

Exemplary viscosity controlling agents include gelatin, alginic acid,agarose, agar, carrageenan, gums (e.g., xanthan gum, locust bean gum,guar gum, tragacanth, gum karaya, and natural gum), and polysaccharides(e.g., methyl cellulose, glucomannan, galactomannan, and gulaman).

Exemplary vitamins include, but are not limited to, water-solublevitamins (e.g., vitamins B1-5, 6, 7, 9, and 12 and C; and fat-solublevitamins (e.g., vitamins A, D, E, or K).

For a patient with dysphagia, the viscosity of the solution ordispersion could be an important consideration. Patients with dysphagiatypically require restriction of their diet to foods with appropriateviscosity. According to the National Dysphagia Diet, diets can includeliquids or semi-solids that are categorized as being thin (1-50 cP),nectar-like (51-350 cP), honey-like (351-1750 cP), or spoon thick (>1751cP) (The National Dysphagia Diet Task Force, The National DysphagiaDiet: Standardization for Optimal Care. Chicago, Ill., American DieteticAssociation; 2002). The viscosity of the solution or dispersion hereincan be any useful range (e.g., 1-450 cP, 1-1,000 cP, 1-2,000 cP,1-200,000 cP, 50-1,000 cP, 50-2,000 cP, 500-100,000 cP, 1,000 to 200,000cP, or 50,000 to 200,000 cP). In one example, the viscosity of thesolution or dispersion is from 1 to 450 cP. In another example, theviscosity of the solution or dispersion is from 50,000 to 200,000 cP.

The compositions may optionally contain colorants, flavoring agents,sweeteners, or taste masking agents in order to provide a more palatablepreparation. Exemplary colorants include titanium dioxide and dyes thatcan be found in Kirk Othmer Encyclopedia of Chemical Technology, Vol 5,Fourth edition, August 2009, pages 837-884. Exemplary flavoring agentsinclude peppermint, menthol, orange, lemon, mint, cinnamon, cherry,lime, vanilla, tangerine, and, by incorporation, other flavoringsdescribed in National Academy of Sciences—National Research Council,“Chemicals Used in Food Processing,” Publication 1274, pp. 63-258(1965). Exemplary sweeteners include peptides ofL-aspartylyphenylalanine methyl ester; water soluble sweeteners,including stevia saccharin salts (e.g., steviol glycosides, such asRebiana, which contains mainly rebaudioside A), cyclamate salts,acefulfam-K, aspartame, sucralose, and glycyrrhizanatcs; naturalsweeteners, including glucose, xylose, ribose, mannose, fructose,dextrose, sorbitol, and mannitol; and protein based sweeteners, such asthymidine and monellin. Exemplary taste masking agents include colloidalpolysaccharides, including sodium alginate; and other taste maskingagents, such as xanthum gum, carageenan, hydroxypropylmethyl cellulose,methyl cellulose, microcrystalline cellulose, and sodium carboxy methylcellulose.

The method can include a number of post-processing steps. For example,the powdered composition can be further sterilized, such as by treatmentwith heat, an autoclave, or plasma oxidation; pulverized, such as byusing a grinder or a mill; lyophilized.

Further modifications to the methods described herein can be include anymethod well-known in the pharmaceutical art, for example, as describedin “Remington: The Science and Practice of Pharmacy” (20th ed., ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins).

The powdered composition can be characterized using various methodsknown to a skilled person in the arts. The characteristics of the powderwithin the powdered composition can be readily determined using anynumber of methods, including powder diffraction, light scattering, andmicroscopy (such as atomic force microscopy and scanning tunnelingmicroscopy). The size of the powder can be determined by any usefulmethod, including the determination of mesh size. The viscosity can bedetermined by any useful method, including a rheometer or a viscometer.

Furthermore, to determine the amount of pharmaceutically active compoundbound to the peptide, the peptide may be digested from the compound todetermine the exact composition by any useful method (e.g., HPLC method;mass spectrometry, such as electro spray mass spectrometry; or otheranalytical methods commonly employed by the pharmaceutical industry).

The concentration of one or more of the compounds in the formulationwill vary depending on a number of factors, including the dosage of thedrug to be administered, and the route of administration. Optimizationof the appropriate dosages can readily be made by the skilledpractitioner in light of the pharmacokinetics of the compound orcombination of compounds used in the composition. Factors to beconsidered in setting dosages include the compound's specific activity;the severity of the condition or symptoms of the patient; the age,condition, body weight, sex, and diet of the patient; the use (or not)of concomitant therapies; and other clinical factors.

Administration may be one or multiple times daily, weekly (or at someother multiple day interval) or on an intermittent schedule, with thatcycle repeated a given number of times (e.g., 2-10 cycles) orindefinitely. Alternatively, the compositions may be administered assymptoms occur.

The compositions are typically administered daily. In one embodiment,the composition comprises between 1% to 30% (w/w) of one or morecompounds and 90% to 99% (w/w) of the protein. In another embodiment,the composition further comprises a protein or a hydrolyzed protein thatis from 500 Da to 1,000,000 Da. In a preferred embodiment, the proteinor hydrolyzed protein is more than 500 kDa.

The composition can include a pharmaceutically active compound andprotein or a hydrolyzed protein useful weight ratio, such as from 1:1 to1:1000 (e.g., 1:1, 1:2, 1:5, 1:10, 1:25, 1:50, 1:100, 1:500, 1:750,1:1000, and other ratios therebetween). Preferable weight ratios includethose from 1:10 to 1:100 (e.g., 1:10 to 1:20, 1:10 to 1:50, 1:20 to1:100). These weight ratios can also be expressed as percentages, wherethe percentage of compound to protein would range between 1% and 10% byweight. Most commonly, the percentage of compound to protein would be inthe range of 1-5%.

The ratio of the pharmaceutically active compound to the protein canalso be expressed in terms of available binding sites of the protein.Typically, the available binding sites in the protein versus amount ofcompound are in great excess, where the range of excess binding sitesmay be in the range of 1,000 to greater than 10,000,000 (e.g., 5,000 to10,000,000; 5,000 to 100,000,000; or 1,000 to 100,000,000).

Typically, the compositions of the invention are kept in the powder formuntil it is time to be administered to the patient, at which point thepowder is mixed with a liquid carrier to form a stable liquidformulation. For example, the powdered composition can be admixed in anyof a variety of liquids, such as water or milk, to form a liquidsolution or dispersion (e.g. suspension, colloid, emulsion, etc.). Inanother example, the composition can be admixed in a semi-solid or softfood product, such as pudding or apple sauce.

The stability of the dispersion may readily be determined by a skilledperson in the pharmaceutical or chemical arts. For example, thedegradation products of the pharmaceutically active compound within thedispersion can be measured as a function of time. In another example,the sedimentation rate can be determined under equilibrium conditions.

Also provided herein are kits comprising the powdered composition. Forexample, the kits comprise a powdered composition, as described herein,a liquid, and instructions on admixing the powdered composition with theliquid. The kit can further include a container that can be used toadmix the powdered composition with the liquid.

The liquid of the kit can be any aqueous solution, such as water or abuffer. The liquid can also include one or more of any of the agentsdescribed herein. Exemplary agents include a solubilizing agent, astabilizing agent, a surfactant, a preservative, a taste masking agent,a sweetener, a flavoring agent, a dispersing agent, a colorant, abuffering agent, an absorption enhancing agent, an antioxidant, or avitamin.

Proteins

As discussed above, the powdered compositions of the invention containone or more pharmaceutically active compounds and a protein. The proteincan be either a single well-characterized protein or a combination ofproteins with similar molecular weights or varying molecular weights,such that acceptable and medically approved pharmacokinetic parametersare obtained.

Pharmacokinetic parameters may readily be determined by a skilled personin the arts. Pharmacokinetic (PK) analysis can be performed bynon-compartmental (model independent) or compartmental methods.Non-compartmental methods estimate the exposure to a drug by estimatingthe area under the curve of a concentration-time graph. Compartmentalmethods estimate the concentration-time graph using kinetic models.Non-compartmental methods are often more versatile in that they do notassume any specific compartmental model and produce accurate resultsalso acceptable for bioequivalence studies.

Non-compartmental PK analysis is highly dependent on estimation of totaldrug exposure. Total drug exposure is most often estimated by Area Underthe Curve (“AUC”) methods, with the trapezoidal rule (numericaldifferential equations) being the most common area estimation method.Due to the dependence on the length of ‘x’ in the trapezoidal rule, thearea estimation is highly dependent on the blood/plasma samplingschedule. For example, the closer time points result in trapezoids thatare more comparable to the actual shape of the concentration-time curve.

Compartmental PK analysis uses kinetic models to describe and predictthe concentration-time curve. PK compartmental models are often similarto kinetic models used in other scientific disciplines, such as chemicalkinetics and thermodynamics. The advantage of compartmental over somenon-compartmental analyses is the ability to predict the concentrationat any time.

However, disadvantages include the difficulty in developing andvalidating the proper model. Compartment-free modeling based on curvestripping does not suffer this limitation. The simplest PK compartmentalmodel is the one-compartmental PK model with intravenous bolusadministration and first-order elimination. The most complicated PKmodels (called PBPK models) rely on the use of physiological informationto ease development and validation.

The concentration-time profile can be constructed by any usefulbioanalytic techniques, where proper bioanalytical methods should beselective and sensitive. Examples of such methods include chemicaltechniques to measure the concentration of drugs in a biological matrix(e.g., plasma); and mass spectrometry to observe low dose and long timepoint data in a biological matrix (e.g., blood or urine) with highsensitivity, such as LC-MS with a triple quadrupole mass spectrometerand/or tandem mass spectrometry.

Certain protein(s) may act as a drug class protein that binds an entireclass of pharmaceutically active compounds. Examples of classes ofpharmaceutically active compounds include statins, a class of lipidlowering agents that typically comprises a pharmacophore of a modifiedhydroxyglutaric acid component; dihydropyridines, a class of calciumchannel blocking agents; angiotensin converting enzyme inhibitors, aclass of molecules used to treat high blood pressure and heart failure;or certain types of protease inhibitors, a class of molecules used totreat AIDs related diseases.

A drug class protein can be determined using a variety of methods. Forexample, a certain protein can be chosen to bind a certain pharmacophorepresent in a class of pharmaceutically active compounds. As statinstypically have a pharmacophore of a modified hydroxyglutaric acidcomponent, a drug class protein could include positively charged aminoacids that would form an ionic bond with the hydroxyglutaric acidcomponent. Thus, each drug chemical class may have a specific drug classprotein as a preferred binding partner in a complex.

However, specific drug class proteins are not always necessary. Proteinsinclude those from any sources (e.g., natural or synthetic); those withmultiple binding sites for cationic interactions, anionic interactions,or other neutral tight binding interactions; or those with pockets oflipophilic amino acids (e.g., glycine, alanine, valine, leucine,isoleucine, methionine, proline, phenylalanine, tyrosine, or tryptophan)or hydrophilic amino acids (e.g., serine, threonine, aspartic acid,glutamic acid, lysine, arginine, histidine, asparagine, or glutamine).For example, some proteins contain sites that allow for non-specificbinding of all types of compounds. Preferably, the interaction betweenthe protein and the therapeutic agent is a non-covalent interaction.Examples of such proteins include gelatin, casein, whey protein,albumin, and soy protein.

Proteins of particular interest to this method are gelatin, such as typeA gelatin and type B gelatin. Examples of gelatin-based compositionsinclude Jell-O®, which can be formed with varying viscosity. Anotherprotein is whey protein, which can refer to one or more proteins foundin whey, including alpha-lactalbumin, beta lactoglobulin, bovine serumalbumin, glycomacropeptide (casein-derived protein), immunoglobulins(e.g., IgG1, IgG2, IgGA, and IgM), lactoferrin, and lactoperoxidase.Whey protein can also include other agents, such as lactose, calcium, orlipids (e.g., sphingolipids or conjugated linoleic acid). Whey may befurther defined as a concentrate or isolate. Yet another particularprotein is albumin, such as bovine serum albumin or human serum albumin.Albumin may be present as a concentrate or isolate. In addition, albuminmay be supplied in any form, such as non-fat dried milk powder. Anotherprotein of particular interest is soy protein, which can refer to one ormore proteins found in soy, including β-conglycinin (or a 7S form) orglycinin (a 11S form).

The composition can include any combination of one or more proteins orhydrolyzed proteins. For example, the composition includes both wheyprotein and casein, soy protein and casein, whey protein and albumin, orwhey protein and soy protein.

For controlled release of the compound, casein could be used as theprotein or as one of the proteins within a combination of proteins.Casein tends to form a gel within the stomach and can be used to releasea compound slowly over time.

As described herein, the proteins can be hydrolyzed leading to smallerhydrolyzed protein with greater water solubility and greater specificityfor a drug or drug class. A hydrolyzed protein includes any proteinfragment that is shorter than a full length protein, such as fragmentcontaining between 1% to 99% of the amino acids in the full lengthprotein (e.g., between 10%-95%, 10%-75%, 10%-50%, 20%-95%, 20%-75%,20%-50%, 30%-95%, 40%-95%, or 50%-95%). The smaller fragments will alsobe less likely to cause antigenic responses. In addition, hydrolyzedproteins are more likely to have water soluble dispersalcharacteristics. Furthermore, in some embodiments the protein may bedenatured or partially denatured.

The protein or hydrolyzed protein can be of any useful size, such asfrom 500 to 10,000,000 Da (e.g., 500 Da to 100,000 Da, 500 Da to 500,000Da, 500 Da to 10,000,000 Da, 1,000 Da to 100,000 Da, 1,000 Da to 500,000Da, and 1,000 Da to 10,000,000 Da). In all cases, the size of theprotein varies from a full length protein to a hydrolyzed protein. Ahydrolyzed protein can be prepared by any method that breaks one or morepeptide bonds (or amide bonds) in the full length protein. Peptide bondscan be broken by hydrolysis (e.g., treatment with one or more of anacid, base, heat, or bacterial extract in water or a buffer); bycomplete or limited proteolysis, such as by the use of enzymes (e.g.,pepsin, trypsin, papain, bromelain, ficin, thermolysin, rennet,Alcalase®, Neutrase®, Protamex®, Novo-Pro™ D, or Flavourzyme®); or anycombination thereof. The degree of hydrolysis can be determined by anymethod, such as column chromatography, molecular sieving, or directsequencing of the peptide or hydrolyzed peptide.

Most commonly, hydrolyzed proteins are formed by partial enzymatichydrolysis. Thus, the hydrolyzed protein may be fragments as small as 5amino acids with a molecular weight as small as 500 Da. A most preferredsize for the protein will be a size that allows for good solubilizationin a solution or dispersion; or that will form a homogenous suspensionin a solution or dispersion. The protein may vary in size based onsolubility criteria and the overall charge surface density of theprotein.

The protein may also be of a larger nature and be used as in asuspension (e.g., in a semi-solid food product). When larger proteinsare used, these proteins may be hydrolyzed by using acidic conditions orby using heat. For example, heat or acidic conditions can be used forcasein to determine which caseinate form will bind and trap thepharmaceutically active compound. When using casein, the compositionwill typically result in a slow release formulation of the compound.Thus, the nature of the protein can allow for quick release forms, whichcan be altered to produce slow release forms.

In addition to size, other physical characteristics of the protein canbe considered. Ideally, the pharmaceutically active compound is tightlybound to the protein. The bond between the compound and the protein canbe covalent and, more preferably, non-covalent (e.g., by anelectrostatic bond, by van der Waals interactions, by virtue of multiplenon-covalent binding regions, by lipophilic interaction, or by LogP-based attractions). In some cases, a specific compound having a freehydroxyl may be bound covalently to a free carboxyl function on thepeptide, thereby forming an ester bond between the compound and thepeptide. Eventually, the ester bond is hydrolyzed when thecompound-protein complex is exposed to the acid environment of thestomach. In addition, the peptide will be digested in the stomach bygastric proteases and to some extent by intestinal proteases. Thisaction will free the bound compound and allow for its normal absorptioninto the gastrointestinal tract.

Pharmaceutically Active Compounds

Suitable pharmaceutically active compounds or combinations thereof foruse in the compositions and methods of the invention generally includethose that are typically less than 500 Da. Suitable compounds includethose in the contemporary editions of the Physician's Desk Reference(PDR), the Merck Manual, or a medical text book, Goodman and Gilman.

The compounds may be optionally administered as a pharmaceuticallyacceptable salt, such as a non-toxic acid addition salts or metalcomplexes that are commonly used in the pharmaceutical industry.Examples of acid addition salts include organic acids such as acetic,lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic,palmitic, suberic, salicylic, tartaric, methanesulfonic,toluenesulfonic, or trifluoroacetic acids or the like; polymeric acidssuch as tannic acid, carboxymethyl cellulose, or the like; and inorganicacid such as hydrochloric acid, hydrobromic acid, sulfuric acidphosphoric acid, or the like. Metal complexes include zinc, iron, andthe like.

Examples of compounds or combinations thereof include:

5-HT_(1A) receptor agonists (e.g., buspirone and tandospirone);

5-HT₂ receptor antagonists, such as 5-HT₂, 5-HT_(2B) and 5-HT₂c receptorantagonists (e.g., sarpogrelate, asenapine, clozapine, and olanzapine);

α-adrenergic receptor agonists (e.g., phenylephrine, pseudoephedrine,and oxymetazoline);

α-adrenergic receptor antagonists, also known as alpha-adrenoceptors orα-blockers (e.g., phenoxybenzamine, phentolamine, prazosin, anddoxazosin);

β-adrenergic receptor agonists (e.g., salbutamol, albuterol,levalbuterol, terbutaline, bitolterol, salmeterol, formoterol, andbambuterol);

β-adrenergic receptor antagonists, also known as beta-adrenoceptors orβ-blockers (e.g., carvedilol, propranolol, nadolol, timolol, pindolol,labetalol, metroprolol, atenalol, esmolol, and acebutolol);

acetylcholinesterase inhibitors (e.g., donepezil, galantamine,rivastigmine, and tacrine);

anesthetics (e.g., physostigmine, neostigmine, and procaine);

angiotensin receptor antagonists (e.g., valsartan, losartan, olmesartan,and irbesartan);

angiotensin converting enzyme inhibitors (e.g., captopril, enalapril,lisinopril, and ramipril);

antibiotics, including penicillins (e.g., amoxicillin, ampicillin, andcloxicillin), cephalosporins (e.g., cetazolin, cefixime, ceftazidime,and cefiriaxone), polymixins, quinolones (e.g., ciprofloxacin,levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin),sulfonamides (e.g., sulfaisodimidine, sulfanilamides, sulfadiazine,sulfamethoxazole, sulfadimethoxine, and sulfnamethoxypyridazine),glycopeptides (e.g., vancomycin), aminoglycosides (e.g., streptomycin,neomycin, spectinomycin, gentamicin, and kanamycin), macrolides (e.g.,erythromycin, azithromycin, and ketolide), tetracyclines (e.g.,doxycycline, chlortetracycline, mecycline, and tigecycline), cycliclipopeptides (e.g., daptomycin), oxazolidinones (e.g., linezolid andtorezolid), and combinations with other therapeutic agents (e.g.,amoxicillin with clavulanate);

anticholinergic agents (e.g., ipratropium bromide, oxitropium bromide,and tiotropium);

anticoagulants (e.g., heparin, coumadin, enoxaparin, warfarin, apixaban,and rivaroxaban);

anticonvulsants (e.g., gabapentin, topiramate, hydantoin,benzodiazepines, zonisamide, valproic acid, ethosuximide, carbamazepine,primidone, lamotrigine, felbamate, levetiracetam, and tiagabine);

antidepressants (e.g., fluvoxamine, paroxetine, sertraline,desvenlafaxine, duloxetine, milnacipran, venlafaxine, bupropion, andatomoxetine);

antidiabetic agents (e.g., insulin, metformin, glipizide, glyburide,glimepiride, gliclazide, repaglinide, nateglinide, rosiglitazone,pioglitazone, miglitol, acarbose, liraglutide, vildagliptin, andsitagliptin);

antifungal agents (e.g., clotrimazole, ciclopirox, ketoconazole,itraconazole, fluconazole, abafungin, terbinafine hydrochloride,amorolfine, naflifine, and butenafine);

antiinflammatory agents (e.g., aspirin, diclofenac, and cyclooxygenaseinhibitors, such as ibuprofen, ketoprofen, and naproxen);

antihistamines (e.g., carbinoxamine, clemastine, dimenhydrinate,pyrilamine, tripelennamine, chlorpheniramine, brompheniramine,hydroxyzine, cyclizine, acrivastine, cetririzine, azelastine,loratadine, fexofenadine, doxepin, diphenhydramine, and all tricyclicsthat have antihistaminic activity, such as amitriptyline, imipramine,promethazine, chlorpromazine, and nortriptyline);

antipsychotic agents (e.g., 5-HT_(2A) receptor antagonists, dopamineantagonists, haloperidol, droperidol, chlorpromazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, aripiprazole,trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine,promethazine, chlorprothixene, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, and zotepine);

antiplatelet agents (e.g., abciximab, eptifibatide, tirofiban,clopidogrel, ticlopidine, prasugrel, beraprost, prostacyclin, iloprost,treprostinil, aspirin, ditazole, cloricromen, dipyridamole, andtriflusal);

antithrombotic agents (e.g., aspirin, dipyridamole, clopidogrel,prasugel, and cangrelor);

antiviral agents, including DNA antivirals (e.g., acyclovir,valaciclovir, ganciclovir, famciclovir, vidarabine, foscarnet,tromantadine, rifampicin, entecavir, lamivudine, telbivudine, adefovir,stavudine, zidovudine, abacavir, and tenofovir), general nucleic acidinhibitors (e.g., cidofovir, interferon alfa-2b, peginterferon alfa-2a,ribavirin, and taribavirin), and RNA antivirals (e.g., boceprevir,telaprevir, pleconaril, arbidol, amantadine, rimantadine, oseltamivir,zanamivir, peramivir, and laninamivir);

anxiolytic agents (e.g., alprazolam, chlordiazepoxide, clonazepam,diazepam, lorazepam, benzodiazepines, and 5-HT_(1A) receptor agonists);

cholesterol-lowering drugs, such as statins (e.g., atorvastatin,pravastatin, simvastatin, and rusovastatin);

dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline,lisuride, pergolide, piribedil, pramipexole, and ropinirole);

dopamine antagonists (e.g., amisulpride and sertindole);

eicosanoid inhibitors (e.g., zafirlukast, zileuton, and montelukast);glucocorticoids (e.g., beclomethasone, hydrocortisone, cortisoneacetate, prednisone, prednisolone, methylprednisolone, dexamethasone,betamethasone, triamcinolone, fludrocortisone acetate,deoxycorticosterone acetate, and aldosterone);

ion channel blocking agents, such as calcium channel blockers (e.g.,nifedipine, amlodipine, felodipine, flunarizine, diltiazem, verapamil,nifedipine, and nimodipine) or sodium channel blockers (e.g.,procainamide, quinidine, ajmaline, disopyramide, prajmaline, sparteine,lidocaine, mexiletine, tocainide, aprindine, encainide, flecainide,lorcainide, moricizine, and propafenone);

monoamine oxidase B inhibitors (e.g., selegiline and rasagiline);

N-methyl d-aspartate (NMDA) receptor antagonist (e.g., dextromethorphanand memantine);

norepinephrine reuptake inhibitor (e.g., reboxetine, duloxetine, andamitriptyline);

opioids (e.g., morphine, codeine, meperidine, and oxycodone);

prostaglandins (e.g., epoprostenol and alprostadil);

proton pump inhibitors (e.g., omeprazole, esomeprazole, pantoprazole,lansoprazole, and rabeprazole);

renin antagonist (e.g., aliskiren and antidepressants with reninantagonistic activity, such as citalopram, escitalopram, andfluoxetine);

serotonergics (e.g., a selective serotonin reuptake inhibitor, aserotonin agonist, and a serotonin partial agonist);

steromidal anti-inflammatory agents (e.g., hydrocortisone, cortisoneacetate, fludrocortisone acetate, deoxycorticosterone acetate,prednisone, prednisolone, methylprednisolone, dexamethasone,betamethasone, triamcinolone, beclometasone, and aldosterone);

tricyclics (e.g., amitriptyline and imipramine);

thromboxane A2 agonists (e.g., ramatroban and seratrodast); and

triptans (e.g., almotriptan, eletriptan, frovatriptan, naratriptan,rizatriptan, sumatriptan, and zolmitriptan);

vasodilators (e.g., glyceryl trinitrate, isosorbide dinitrate,isosorbide mononitrate, linsidomine, molsidoymine, pentacrythritoltetranitrate, and flosequinan); and

miscellaneous drugs, such as pentoxifylline and cilostazol.

Particularly favored compounds or combinations thereof include thosegenerally taken by the elderly or by those with dysphagia. Examples ofcompounds taken by the elderly include drugs for the treatment of CNSdisorders, such as Parkinson's Disease, Alzheimer's Disease, dementia,Huntington's Chorea, and endogenous depression; cardiovascular disease,such as congestive heart failure, peripheral artery disease,arrhythmias, and hypertension; pulmonary diseases, such as asthma andchronic obstructive disease; infections of a viral bacterial or fungalnature; gastrointestinal diseases, such as gall bladder disease,diverticulolitis, irritable bowel disease, gastroesophageal reflux, andgastric and intestinal ulcers; urinary disease, such as urinaryincontinence, women's health issues, such an osteoarthritic condition;men's health issues, such as benign prostate hyperplasia; cancers, suchas head and neck, lung, breast, and colon; and endocrine disordersassociated with pituitary and adrenal function.

The pharmaceutically active compounds include any type of compound orcombinations thereof to treat one or more common diseases of differentor same etiology. These compounds and combinations include compounds totreat CNS disorders; one or more drugs to treat cardiovascular disease;one or more drugs to treat pain and inflammation; one or more drugs totreat gastrointestinal disease; one or more antibiotics, antiviralagents or antifungal agents to treat infections; or one or morecompounds to treat complex multiple independent disease states.

Examples of compounds to treat CNS disorders (e.g., Alzheimer's disease,dementia, and Parkinson's disease) include acetylcholinesteraseinhibitors, NMDA receptor antagonists, antipsychotic agents, anxiolyticagents, levodopa, dopamine agonists, monoamine oxidase B inhibitors;compounds to treat pulmonary diseases (e.g., asthma) includeβ-adrenergic receptor agonists, anticholinergic agents, eicosanoidinhibitors, and inhaled or oral glucocorticoids; compounds to treatcardiovascular disease (e.g., heart failure) include β-adrenergicreceptor antagonists, acetylcholinesterase inhibitors, angiotensinreceptor antagonists, and vasodilators; compounds to treat pain andinflammation include antiinflammatory agents, anesthetics, and opioids;compounds to treat gastrointestinal diseases (e.g., irritable boweldisease, gastroesophageal reflux, or gastric and intestinal ulcers)include serotonergics, tricyclics, anticholinergic agents, opiates,proton pump inhibitors, and H₂ receptor antagonist (e.g., cimetidine);and compounds to treat vascular diseases include antithrombotic agents,anticoagulants, cholesterol-lowering drugs, or antiplatelet agents,where examples of these compounds are provided herein.

Other suitable compounds or combinations thereof include those takenfrequently, for example, at least once a day. Examples of such compoundsinclude an alpha adrenoceptor agonist (e.g., phenylephrine orpseudoephedrine); an analgesic (e.g., physostigmine, neostigmine, orprocaine); an anesthetic; an anticonvulsant (e.g., gabapentin); ananticholinergic compound; an antihistamine (e.g., diphenhydramine); anantiinflammatory compound, such as a non-steroidal antiinflammatorydrug; a beta 2 receptor antagonist (e.g., propranolol); a cyclooxygenaseinhibitor (e.g. ibuprofen, ketoprofen, or naproxen); an ion channelblocking compound, such as a sodium channel blocker or a calcium channelblocker; a N-methyl d-aspartate (NMDA) receptor antagonist (e.g.,dextromethorphan); a norepinephrine reuptake inhibitor; a selectiveserotonin reuptake inhibitor; a serotonin agonist; a serotonin partialagonist; a tricyclic (e.g., amitriptyline or imipramine); and/or atriptan (e.g., almotriptan, eletriptan, frovatriptan, naratriptan,rizatriptan, sumatriptan, or zolmitriptan).

Combinations of two or more compounds can be administered to a patient.Exemplary combinations include a combination of compounds for thetreatment of heart failure or vascular disease; two antibiotics; or twocompounds for the treatment of mixed therapeutic needs, such ashypertension and heart failure or asthma and vascular disease.

Pharmaceutically active compounds also encompass any nutraceutical andcombinations of substances that have therapeutic or preventative healthpurposes. Examples of nutraceuticals include niacin, carnitine,acetylcarnitine, co-enzyme Q-10, policosanol, vitamins, and naturalantioxidants, such as lipoic acid, vitamin E, and vitamin C

Further features and advantages of this invention are furtherillustrated by the following examples, which are in no way intended tobe limiting thereof.

Examples Example 1: General Preparation of Liquid Formulation

In a vessel, a protein with water-soluble dispersal characteristics,such as a hydrolyzed whey protein, was brought into a solution or asuspension with an aqueous solvent, such as water or a buffer. Aconcentrate of drug was then prepared, using standard and specific andknown methods, to bring the drug into solution. The protein solution waswarmed to approximately 37° C. and the drug concentrate is slowly addedwith constant stirring. The drug was allowed to bind to equilibrium withthe protein. The protein was in far excess to the drug product, thusdriving the drug product to be largely bound at equilibrium. Typically,the available binding sites in the protein versus amount of drug to bebound are in great excess, where the range of excess binding sites maybe in the range of 1,000 to greater than of 10,000,000. In terms ofweight considerations, the percent drug to protein would range between1% and 10% by weight. Most commonly, drug product to protein productwould be in the range of 1-5%. After achieving equilibrium, theprotein:drug complex was cooled to minimally room temperature or 23′C,filtered, and resuspended in an aqueous solution. Colorants,preservatives, taste masking agents, and other agents can be added tothe aqueous solution to induce optimal viscosity.

Example 2: Fentanyl Binding to Bovine Serum Albumin (BSA) as Measured byEquilibrium Dialysis

A standard two-compartment equilibrium dialysis method was used tomeasure the binding of fentanyl to BSA. In compartment “A” was placed a0.78 mM fentanyl solution and 95 mg/ml BSA in a 25 mM phosphate bufferat pH 7. In compartment “B” was placed a 25 mM phosphate buffer at pH 7.Compartments A and B were allowed to come to equilibrium over a four-dayperiod at room temperature. Fentanyl concentrations were measured afterdiluting samples 1/10,000 using an Agilent 6460 triple quadrupole massspectrometer (Agilent Technologies, Santa Clara, Calif., USA) using thefollowing protocol, and the results are reported in Table 3 below:

Sample Preparation.

Plasma samples (50 Id.) were mixed with acetone containing 1% pyridine(200 μL) in a pre-tared centrifuge tube. All samples were centrifuged at4° C. for 10 minutes, 15,000 rpm. After recording sample weights,supernatants were transferred to a second pre-tared centrifuge tube andthe volume was reduced in vacuo by use of a SpeedVac concentrator. Theresidual acetone-free sample volumes were determined by weight. Theaverage sample volumes following concentration were approximately 40 μL.

Analysis by LC-MS/MS.

A 5 μL aliquot of each processed sample was subjected to liquidchromatography on a 1200 series Agilent liquid chromatograph interfacedwith an Agilent 6460 Triple Quad LC/MS. The chromatographic conditionsare summarized in Table 1. Detection of either fentanyl or ketoprofenwas by MRM. The precursor ion for fentanyl was 337 m/z and product ionswere 188 and 105 m/z (m+1). The precursor ion for ketoprofen was 255 m/zand product ions were 209 and 105 m/z (m+1). The mass spectroscopicconditions are summarized in Table 2.

TABLE 1 HPLC Assay Conditions Injection 5 μl Volume Run Time 4 minMobile Phases “A” 0.1% formic acid in water “B” 0.1% formic acid inacetonitrile Gradient 0-0.5 min 2% “B” 0.51-2.5 min 70% “B” 2.51-4 min2% “B” Flow Rate 0.8 ml/min Column Agilent Zorbax Eclipse XDB-C18 RapidResolution HT, 4.6 × 50 mm, 1.8 micron, 600 Bar, PN 927975-902 ColumnTemp. 60° C.

TABLE 2 Mass Spectroscopic Conditions Ion Source ESI+Agilent Jet StreamScan Type MRM Polarity Positive Scan Segments Fentanyl Prec Ion 337.2Prod Ion 188.1 Frag 136 V CE 18V (Qual Prod 105, CE 38V) Ketoprofen PrecIon 255 Prod Ion 104.9 Frag 100 CE 10 (Qual Prod 209, CE 20) Gas Temp300° C. Gas Flow 5 l/min Nebulizer 45 psi Sheath Gas 250° C. Temp SheathGas 11 l/min Flow Capillary 3500 V Nozzle Voltage 500 V

The results, provided in Table 3 below, indicated that following threeseparate determinations, Fentanyl was shown to bind to BSA protein.

TABLE 3 Fentanyl Binding to BSA Protein Fentanyl BSA Binding SampleCompartment (μM) (mg/ml) Preference A/B Control (no A 391 95 0.95 BSA) B410 0 Determination 1 A 544 95 4.0 B 136 0 Determination 2 A 639 95 4.4B 145 0 Determination 3 A 552 95 2.45 B 225 0

Example 3: Antinociception (Analgesia) in Mice Given Fentanyl Formulatedin Water or Bound to BSA

Mice weighing on average 32 grams were gavaged p.o. (orally) withfentanyl prepared either in a water solution or following binding toBSA. Equimolar amounts of fentanyl base were used in each formulation.Analgesia was assessed by tail withdrawal reflex using a water stimulusat 55° C. The results are provided in FIGS. 1A, 1B and 2.

The data provided in FIGS. 1A and 1B demonstrate that both fentanylformulated in water or formulated in a bound state to BSA is equallypotent to induce analgesia in a dose response relationship (each datapoint provided in FIGS. 1A and 1B represents three separatedeterminations). FIG. 2 presents a direct comparison of fentanylformulated in water with fentanyl bound to BSA (as provided in FIGS. 1Aand 1B). In these experiments, fentanyl bound to BSA produced a largeranalgesic response (see data for 1 and 3.2 mg/kg fentanyl in water ascompared to the BSA formulation).

Example 4: Ketoprofen Binding to Bovine Serum Albumin (BSA) as Measuredby Equilibrium Dialysis

A standard two-compartment equilibrium dialysis method was used tomeasure ketoprofen binding to BSA. In compartment “A” was placed a 0.608mM solution of ketoprofen with 143 mg/ml BSA in 0.9% NaCl. Incompartment “B” was placed 0.9% NaCl. Compartments A and B were allowedto come to equilibrium over a three-day period at room temperature.Ketoprofen concentrations were measured after diluting samples 1/1,000using an Agilent 6460 triple quadrupole mass spectrometer (AgilentTechnologies, Santa Clara, Calif., USA) (see protocol described above).The results for four determinations are provided in Table 4 below.

TABLE 4 Ketoprofen Binding to BSA Protein Binding Ketoprofen BSAPreference Sample Compartment (μM) (mg/ml) A/B Control (no A 280 0 NoBinding BSA) B 325 0 Determination 1 A 515 143 100% Bound B 0 0Determination 2 A 696 143 100% Bound B 0 0 Determination 3 A 481 143100% Bound B 0 0 Determination 4 A 532 143 100% Bound B 0 0

Example 5: Comparison of Pharmacokinetic Absorption Profile forKetoprofen Formulated in 0.9% NaCl Vs. Ketoprofen Bound to BSA Solution

Mice weighing on average 32 grams were gavaged with 1, 3.2, or 10 mg/kgketoprofen formulated in either 0.9% NaCl or bound to BSA at 143 mg/ml.At 30 minutes post-ketoprofen dosing, mice were anesthetized withisoflurane, the chest was opened and blood was taken by cardiac puncturefrom the left ventricle using a 1 ml syringe (22G 1 inch needle).

Blood was placed in 1 ml of EDTA treated microcontainers and stored onice. Plasma separated from whole blood using a 1500 rpm spin for 15minutes. Free plasma was stored on ice and analyzed for the presence ofketoprofen using a Agilent 6460 triple quadrupole mass spectrometer(Agilent Technologies, Santa Clara, Calif., USA). The absorptionprofiles for ketoprofen administered in saline and for ketoprofen boundto BSA were determined and are provided in FIG. 3. Each data point isthe average of three separate determinations. At 1 mg/kg and 3.2 mg/kgthere was no difference between the absorption of ketoprofen bound toBSA versus ketoprofen administered in saline. The data for high doseketoprofen (10 mg/kg) indicate that BSA facilitates the absorption ofketoprofen and may increase the bioavailability of the drug.

All publications, patent applications, and patents mentioned in thisspecification are herein incorporated by reference.

Various modifications and variations of the described method and systemof the invention will be apparent to those skilled in the art withoutdeparting from the scope and spirit of the invention. Although theinvention has been described in connection with specific desiredembodiments, it should be understood that the invention as claimedshould not be unduly limited to such specific embodiments. Indeed,various modifications of the described modes for carrying out theinvention that are obvious to those skilled in the fields of medicine,pharmacology, or related fields are intended to be within the scope ofthe invention.

What is claimed is:
 1. A method of administering a pharmaceuticallyactive compound to a patient, the method comprising the steps of: (a)providing a powdered composition comprising a pharmaceutically activecompound and a protein or a hydrolyzed protein, wherein the protein orthe hydrolyzed protein is from 500 Da to 10,000,000 Da; (b) mixing thepowdered composition with a liquid or semi-solid to form a stablesolution or dispersion in which the protein or the hydrolyzed protein isbound to the pharmaceutically active compound; and (c) orallyadministering the solution or dispersion to the patient.
 2. The methodof claim 1, wherein the pharmaceutically active compound and the proteinor the hydrolyzed protein are present in a ratio of from 1:1 to 1:1,000.3. The method of claim 1, wherein the composition comprises 1% to 30%(w/w) the pharmaceutically active compound and 90% to 99% (w/w) of theprotein or the hydrolyzed protein.
 4. The method of claim 3, where theprotein or the hydrolyzed protein is from 500 Da to 1,000,000 Da.
 5. Themethod of claim 1, wherein the composition is denatured or partiallydenatured.
 6. The method of claim 1, wherein the size of the powder isfrom 1 to 100 mesh.
 7. The method of claim 1, wherein the liquid iswater or an aqueous solution.
 8. The method of claim 1, wherein theviscosity of the dispersion is from 1 cP to 450 cP.
 9. The method ofclaim 1, wherein the viscosity of the dispersion is from 50,000 cP to200,000 cP.
 10. The method of claim 1, wherein the pharmaceuticallyactive compound is less than 500 Da.
 11. The method of claim 1, whereinthe pharmaceutically active compound is one or more of a 5-HT_(1A)receptor agonist, a 5-HT₂ receptor antagonist, an α-adrenergic receptoragonist, an α-adrenergic receptor antagonist, a β-adrenergic receptoragonist, a β-adrenergic receptor antagonist, an acetylcholinesteraseinhibitor, an anesthetic, an angiotensin receptor antagonist, anangiotensin converting enzyme inhibitor, an antibiotic, ananticholinergic agent, an anticoagulant, an anticonvulsant, anantidepressant, an antidiabetic agent, an antifungal agent, anantiinflammatory agent, an antihistamine, an antipsychotic agent, anantiplatelet agent, an antiviral agent, an anxiolytic agent, acholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, aneicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, amonoamine oxidase B inhibitor, an N-methyl d-aspartate receptorantagonist, a norepinephrine reuptake inhibitor, a prostaglandin, aproton pump inhibitor, a renin antagonist, a serotonergic, a steroidalanti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, atriptan, a vasodilator, or a nutraceutical.
 12. The method of claim 1,wherein the protein or the hydrolyzed protein is one or more of gelatin,casein, whey protein, albumin, or soy protein.
 13. The method of claim12, wherein the protein or the hydrolyzed protein is gelatin selectedfrom the group consisting of type A gelatin and type B gelatin.
 14. Themethod of claim 12, wherein the protein or the hydrolyzed protein iswhey protein selected from the group consisting of alpha-lactalbumin,beta lactoglobulin, bovine serum albumin, a glycomacropeptide,immunoglobulin, lactoferrin, and lactoperoxidase.
 15. The method ofclaim 12, wherein the protein or the hydrolyzed protein is albuminselected from the group consisting of bovine serum albumin and humanserum albumin.
 16. The method of claim 12, wherein the protein or thehydrolyzed protein is soy protein selected from the group consisting ofβ-conglycinin and glycinin.
 17. The method of claim 12, wherein theprotein or the hydrolyzed protein comprises from 70% to 95% (w/w) ofwhey protein or from 80% to 95% (w/w) of casein.
 18. The method of claim1, wherein the composition further comprises one or more agents selectedfrom the group consisting of an absorption enhancing agent, anantimicrobial, an antioxidant, a buffering agent, a colorant, adispersing agent, a flavoring agent, a preservative, a solubilizingagent, a stabilizing agent, a surfactant, a sweetener, a taste maskingagent, a viscosity controlling agent, and a vitamin.
 19. The method ofclaim 18, wherein the agent is the absorption enhancing agent selectedfrom the group consisting of achitosan, type A gelatin, and type Bgelatin.
 20. The method of claim 18, wherein the agent is theantimicrobial selected from the group consisting of methylparaben,propylparaben, sodium benzoate, propyl benzoate, sodium sorbate,potassium sorbate, and calcium sorbate.
 21. The method of claim 18,wherein the agent is the buffering agent selected from the groupconsisting of citric acid, malic acid, tartaric acid, phosphoric acid,and pharmaceutically acceptable salts thereof.
 22. The method of claim21, wherein the amount of the buttering agent results in the dispersionhaving a pH from 6 to
 8. 23. The method of claim 22, wherein the pH isfrom 6.8 to 7.2.
 24. The method of claim 18, wherein the agent is thedispersing agent selected from the group consisting of apolyvinylpyrrolidine, an alkyhydroxy cellulose, a dextrin, acyclodextrin, and a polyhydroxyalcohol.
 25. The method of claim 18,wherein the agent is the preservative selected from the group consistingof ethylenediaminetetraacetic acid and a 4-hydroxy benzoic ester. 26.The method of claim 18, wherein the agent is the solubilizing agentselected from the group consisting of 200 Da to 1000 Da polyethyleneglycol, sorbitol, a glycol polyol, and dipropylene glycol polyethylene.27. The method of claim 18, wherein the agent is the stabilizing agentselected from the group consisting of glycerin, pentaerythritol, andsodium alginate.
 28. The method of claim 18, wherein the agent is thesurfactant selected from the group consisting of a polyoxylglyceride, acaprylate, a laurate, an oleate, a monoethyl ether, a sorbitan-basednonionic surfactant, a polyoxyethylene sorbitan-based surfactant, anemulsifier blend, and tocopherol polyethyleneglycol 1000 succinate. 29.The method of claim 18, wherein the agent is the sweetener selected fromthe group consisting of an L-aspartylyphenylalanine methyl ester, astevia saccharin salt, a cyclamate salt, acefulfam-K, aspartame,sucralose, a glycyrrhizanate, glucose, xylose, ribose, mannose,fructose, dextrose, sorbitol, mannitol, thymidine, and monellin.
 30. Themethod of claim 18, wherein the agent is the taste masking agentselected from the group consisting of sodium alginate, xanthum gum,carageenan, hydroxypropylmethyl cellulose, methyl cellulose,microcrystalline cellulose, or sodium carboxy methyl cellulose.
 31. Themethod of claim 18, wherein the agent is the viscosity controlling agentselected from the group consisting of gelatin, alginic acid, agarose,agar, carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth,gum karaya, natural gum, methyl cellulose, glucomannan, galactomannan,and gulaman.
 32. A powdered composition comprising: a pharmaceuticallyactive compound, and a protein or a hydrolyzed protein of greater than500 kDa, wherein the composition when admixed with a liquid orsemi-solid forms a stable solution or dispersion suitable for oraladministration in which the protein or the hydrolyzed protein is boundto the pharmaceutically active compound.
 33. The composition of claim32, wherein the pharmaceutically active compound and the protein or thehydrolyzed protein are present in a ratio of from 1:1 to 1:1000.
 34. Thecomposition of claim 32, wherein the composition comprises 1% to 30%(w/w) the pharmaceutically active compound and 90% to 99% (w/w) of theprotein or the hydrolyzed protein.
 35. The composition of claim 32,wherein the composition is denatured or partially denatured.
 36. Thecomposition of claim 32, wherein the size of the powder is from 1 to 100mesh.
 37. The composition of claim 32, wherein the liquid is water or anaqueous solution.
 38. The composition of claim 32, wherein the viscosityof the dispersion is from 1 to 450 cP.
 39. The composition of claim 32,wherein the viscosity of the dispersion is from 50,000 cP to 200,000 cP.40. The composition of claim 32, wherein the pharmaceutically activecompound is greater than 500 Da.
 41. The composition of claim 32,wherein the pharmaceutically active compound is one or more a 5-HT_(1A)receptor agonist, a 5-HT₂ receptor antagonist, an α-adrenergic receptoragonist, an α-adrenergic receptor antagonist, a β-adrenergic receptoragonist, a β-adrenergic receptor antagonist, an acetylcholinesteraseinhibitor, an anesthetic, an angiotensin receptor antagonist, anangiotensin converting enzyme inhibitor, an antibiotic, ananticholinergic agent, an anticoagulant, an anticonvulsant, anantidepressant, an antidiabetic agent, an antifungal agent, anantiinflammatory agent, an antihistamine, an antipsychotic agent, anantiplatelet agent, an antiviral agent, an anxiolytic agent, acholesterol-lowering drug, a dopamine agonist, a dopamine antagonist, aneicosanoid inhibitor, a glucocorticoid, an ion channel blocking agent, amonoamine oxidase B inhibitor, an N-methyl d-aspartate receptorantagonist, a norepinephrine reuptake inhibitor, a prostaglandin, aproton pump inhibitor, a renin antagonist, a serotonergic, a steroidalanti-inflammatory agent, a tricyclic, a thromboxane A2 agonist, atriptan, a vasodilator, or a nutraceutical.
 42. The composition of claim32, wherein the protein or the hydrolyzed protein is one or more ofgelatin, casein, whey protein, albumin, or soy protein.
 43. Thecomposition of claim 42, wherein the protein or the hydrolyzed proteinis gelatin selected from the group consisting of type A gelatin and typeB gelatin.
 44. The composition of claim 42, wherein the protein or thehydrolyzed protein is whey protein selected from the group consisting ofalpha-lactalbumin, beta lactoglobulin, bovine serum albumin, aglycomacropeptide, immunoglobulin, lactoferrin, and lactoperoxidase. 45.The composition of claim 42, wherein the protein or the hydrolyzedprotein is albumin selected from the group consisting of bovine serumalbumin and human serum albumin.
 46. The composition of claim 42,wherein the protein or the hydrolyzed protein is soy protein selectedfrom the group consisting of l-conglycinin and glycinin.
 47. Thecomposition of claim 42, wherein the protein or the hydrolyzed proteincomprises from 70% to 95% (w/w) of whey protein or from 80% to 95% (w/w)of casein.
 48. The composition of claim 32, further comprising one ormore agents selected from the group consisting of an absorptionenhancing agent, an antimicrobial, an antioxidant, a buffering agent, acolorant, a dispersing agent, a flavoring agent, a preservative, asolubilizing agent, a stabilizing agent, a surfactant, a sweetener, ataste masking agent, a viscosity controlling agent, and a vitamin. 49.The composition of claim 48, wherein the agent is the absorptionenhancing agent selected from the group consisting of achitosan, type Agelatin, and type B gelatin.
 50. The composition of claim 48, whereinthe agent is the antimicrobial selected from the group consisting ofmethylparaben, propylparaben, sodium benzoate, propyl benzoate, sodiumsorbate, potassium sorbate, and calcium sorbate.
 51. The composition ofclaim 48, wherein the agent is the buffering agent selected from thegroup consisting of citric acid, malic acid, tartaric acid, phosphoricacid, and pharmaceutically acceptable salts thereof.
 52. The compositionof claim 52, wherein the amount of the buffering agent results in thedispersion having a pH from 6 to
 8. 53. The composition of claim 53,wherein the pH is from 6.8 to 7.2.
 54. The composition of claim 48,wherein the agent is the dispersing agent selected from the groupconsisting of a polyvinylpyrrolidine, an alkyhydroxy cellulose, adextrin, a cyclodextrin, and a polyhydroxyalcohol.
 55. The compositionof claim 48, wherein the agent is the preservative selected from thegroup consisting of ethylenediaminetetraacetic acid and a 4-hydroxybenzoic ester.
 56. The composition of claim 48, wherein the agent is thesolubilizing agent selected from the group consisting of 200 Da to 1000Da polyethylene glycol, sorbitol, a glycol polyol, and dipropyleneglycol polyethylene.
 57. The composition of claim 48, wherein the agentis the stabilizing agent selected from the group consisting of glycerin,pentaerythritol, and sodium alginate.
 58. The composition of claim 48,wherein the agent is the surfactant selected from the group consistingof a polyoxylglyceride, a caprylate, a laurate, an oleate, a monoethylether, a sorbitan-based nonionic surfactant, a polyoxyethylenesorbitan-based surfactant, an emulsifier blend, and tocopherolpolyethyleneglycol 1000 succinate.
 59. The composition of claim 48,wherein the agent is the sweetener selected from the group consisting ofan L-aspartylyphenylalanine methyl ester, a stevia saccharin salt, acyclamate salt, acefulfam-K, aspartame, sucralose, a glycyrrhizanate,glucose, xylose, ribose, mannose, fructose, dextrose, sorbitol,mannitol, thymidine, and monellin.
 60. The composition of claim 48,wherein the agent is the taste masking agent selected from the groupconsisting of sodium alginate, xanthum gum, carageenan,hydroxypropylmethyl cellulose, methyl cellulose, microcrystallinecellulose, and sodium carboxy methyl cellulose.
 61. The composition ofclaim 48, wherein the agent is the viscosity controlling agent selectedfrom the group consisting of gelatin, alginic acid, agarose, agar,carrageenan, xanthan gum, locust bean gum, guar gum, tragacanth, gumkaraya, natural gum, methyl cellulose, glucomannan, galactomannan, andgulaman.
 62. A liquid or semi-solid formulation prepared by mixing thepowdered composition of any of claims 32 to 61 with a liquid orsemi-solid.
 63. The liquid formulation of claim 62, wherein the liquidis an aqueous solution.
 64. The liquid formulation of claim 63, whereinthe pH is between 6 and
 8. 65. The liquid formulation of claim 64,wherein the pH is between 6.8 and 7.2.
 66. The liquid formulation ofclaim 62, wherein the viscosity is from 1 cP to 450 cP.
 67. The liquidformulation of claim 62, wherein the viscosity is from 50,000 cP to200,000 cP.
 68. A method for preparing a powdered compositioncomprising: dispersing a protein or a hydrolyzed protein in an aqueoussolution at a first temperature ranging from 10° C. to 50° C. to form aprotein mixture; adding an effective amount of a pharmaceutically activecompound to the protein mixture; before or after the compound has beenadded to the protein mixture, heating the protein mixture to a secondtemperature ranging from 23° C. to 60° C., wherein the amount of theprotein or the hydrolyzed protein is in excess of the effective amountof the compound; cooling the mixture to a third temperature ranging from5° C. to 23° C.; and separating the mixture from the aqueous solution toobtain the powdered composition.
 69. The method of claim 68, wherein theprotein or the hydrolyzed protein is one or more of gelatin, casein,whey protein, albumin, or soy protein.
 70. The method of claim 68,wherein the aqueous solution is water or a buffer.
 71. The method ofclaim 70, wherein the buffer has a pH between 6 and
 8. 72. The method ofclaim 68, wherein the aqueous solution further comprises one or moreagents selected from the group consisting of an absorption enhancingagent, an antimicrobial, an antioxidant, a buffering agent, a colorant,a dispersing agent, a flavoring agent, a preservative, a solubilizingagent, a stabilizing agent, a surfactant, a sweetener, a taste maskingagent, a viscosity controlling agent, and a vitamin.
 73. The method ofclaim 68, wherein the first temperature range is from 20° C. to 25° C.74. The method of claim 68, wherein the second temperature range is from25° C. to 37° C.
 75. The method of claim 68, wherein the thirdtemperature range is from 23° C. to 37° C.
 76. A kit comprising: (a) apowdered composition that can be admixed with a liquid to form a stablesolution or dispersion suitable for oral administration to a patient,said composition comprising: i. 1% to 30% (w/w) of a pharmaceuticallyactive compound and ii. 70% to 99% (w/w) of a protein or a hydrolyzedprotein of greater than 500 kDa, wherein said compound is bound to saidprotein; (b) a liquid; and (c) instructions on admixing the powderedcomposition with the liquid.
 77. The kit of claim 76, wherein thepowdered composition comprises the pharmaceutically active compoundselected from the group consisting of a 5-HT_(1A) receptor agonist, a5-HT₂ receptor antagonist, an α-adrenergic receptor agonist, anα-adrenergic receptor antagonist, a β-adrenergic receptor agonist, aβ-adrenergic receptor antagonist, an acetylcholinesterase inhibitor, ananesthetic, an angiotensin receptor antagonist, an angiotensinconverting enzyme inhibitor, an antibiotic, an anticholinergic agent, ananticoagulant, an anticonvulsant, an antidepressant, an antidiabeticagent, an antifungal agent, an antiinflammatory agent, an antihistamine,an antipsychotic agent, an antiplatelet agent, an antiviral agent, ananxiolytic agent, a cholesterol-lowering drug, a dopamine agonist, adopamine antagonist, an eicosanoid inhibitor, a glucocorticoid, an ionchannel blocking agent, a monoamine oxidase B inhibitor, an N-methyld-aspartate receptor antagonist, a norepinephrine reuptake inhibitor, aprostaglandin, a proton pump inhibitor, a renin antagonist, aserotonergic, a steroidal anti-inflammatory agent, a tricyclic, athromboxane A2 agonist, a triptan, a vasodilator, or a nutraceutical.78. The kit of claim 76, wherein the powdered composition comprises theprotein or the hydrolyzed protein selected from the group consisting ofgelatin, cascin, whey protein, albumin, and soy protein.
 79. The kit ofclaim 76, wherein the liquid comprises one or more agents selected fromthe group consisting of an absorption enhancing agent, an antimicrobial,an antioxidant, a buffering agent, a colorant, a dispersing agent, aflavoring agent, a preservative, a solubilizing agent, a stabilizingagent, a surfactant, a sweetener, a taste masking agent, a viscositycontrolling agent, and a vitamin.